两个伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病家系NOTCH3基因的突变分析  

NOTCH3 gene mutations in two Chinese families featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephaiopathy

作　　者：孙启英[1] 李雯雯[1] 周亚芳[1] 易芳[1] 王建锋 胡雅岑 姚凌雁[1] 周琳[1] 许宏伟[1] 

机构地区：[1]中南大学湘雅医院老年病学神经内科,长沙410008

出　　处：《中华医学遗传学杂志》2017年第6期816-820,共5页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金（81401059,81401060）

摘　　要：目的分析两个伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病（cerebral autosomal dominant arteriopathy with subeortieal infarct and leucoencephalopathy，CADASIL）家系NOTCH3基因的突变情况，为遗传咨询提供依据。方法收集2个临床疑诊为CADASIL家系的患者临床资料，分析其临床特征，并对先证者和家系成员以及100名健康对照者进行NOTCH3基因测序，对发现的突变用PolyPhen-2、SIFT等软件进行功能预测，以明确其致病性。结果两个家系的先证者均为中年起病，临床表现为反复脑缺血性发作、认知功能损害等，头颅磁共振成像显示多发腔隙性脑梗死和广泛的脑白质疏松。DNA测序显示先证者1存在NOTCH3基因第3外显子c．328C〉T（p．Arg110Cys）杂合突变，为已知致病突变，先证者2存在NOTCH3基因第6外显子c．1013G〉C（P．Cys338Ser）杂合突变，尚未见报道。在100名健康对照者中未检测到上述杂合突变。功能预测分析表明c．1013G〉C杂合突变可能对NOTCH3的编码蛋白产生重要的影响。结论两个家系的CADASIL病均由NOTCH3基因突变所致，其中NOTCH3基因第6外显子c．1013G〉C（P．Cys338Ser）杂合突变为cADASIL新的致病突变。Objective To analyze potential mutations of the NOTCH3 gene in two Chinese families featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy （CADASIL）. Methods The two probands and related family members and 100 healthy controls were recruited. Potential mutations of the NOTCH3 gene were screened by PCR and direct sequencing. PolyPhen-2 and SIFT software were used to predict the protein function. Results The conditions of both probands were adult-onset, with main clinical features including recurrent transient ischemic attacks and/or strokes, cognitive impairment. MRI findings suggested multiple cerebral infarcts and severe leukoencephalopathy. A heterozygous mutation c. 328C〉T （p. Arg110Cys）, which was located in exon 3 of the NOTCH3 gene and known as a causative mutation, was identified in proband 1. A novel heterozygous mutation c. 1013 G〉C （p. Cys338Ser） located in exon 6 of the NOTCH3 gene was identified in the proband 2, which was not reported previously. The same mutations were not detected among the 100 unrelated healthy controls. Function analysis suggested that heterozygous mutation c. 1013G〉C can severely affect the functions of NOTCH3 protein. Conclusion Two heterozygous missense mutations in the NOTCH3 gene have been identified in two families affected with CADASIL. The novel heterozygous Cys338Ser mutation in exon 6 of the NOTCH3 gene probably underlies the CADASIL.

关 键 词：伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病 NOTCH3基因 突变 

分 类 号：R394[医药卫生—医学遗传学]